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. Author manuscript; available in PMC: 2024 Apr 2.
Published in final edited form as: Mol Cancer Ther. 2023 Oct 2;22(10):1182–1190. doi: 10.1158/1535-7163.MCT-22-0818

Figure 1. LP-184 cytotoxicity is dependent on prostaglandin reductase 1 (PTGR1).

Figure 1.

(A) Chemical structure of irofulven and its derivative stereoisomers LP-184 and LP-284. Box highlights the critical isomerism of the hydroxyl moiety. (B, C) Correlation of PTGR1 expression and cytotoxicity (IC50, µM) of LP-184 (B) and LP-284 (C) tested in vitro against a panel of NCI-60 cell lines. See also Table S1. Leukemic cell lines with low expression of PTGR1 are colored in red. (D) Normalized (RSEM) expression of PTGR1 mRNA in human cancers (Pan-Cancer Atlas, TCGA). Note lower expression in hematological malignancies (e.g., AML, DLBCL). Purple, pancreatic adenocarcinoma (PAAD). (E, F) PTGR1 depletion with CRISPRi targeting PTGR1 promoter in Panc 03.27 by Western blot (E) and qRT-PCR (F) cell lines. (G) LP-184 exhibits cytotoxicity in strict dependency on PTGR1 expression in Panc 03.27 cells, whereas cytotoxicity of LP-284 stereoisomer is independent of the PTGR1 status. Shown are averaged results of 3 independent repeats; error bars, standard deviations. (H, I) Induction of DNA damage as assessed by phosphorylated form of histone H2AX in Panc 03.27 cells treated with LP-184 (24 hours at 0.5 µM) or its stereoisomer LP-284 (24 hours at 1 µM). Note absence of pH2AX expression in sgPTGR1-depleted cells. Shown, pH2AX bands density normalized to alpha-tubulin in two repeats of Western blot (H) and a representative Western blot membrane (I). (J) Immunofluorecent detection of pH2AX (integrated intensity) in Panc 03.27 cells modified with non-targeting sgRNA (sgControl) or depleted of PTGR1 and treated with LP-184 and LP-284 as in H. See also Supplementary Figure S1.